5 Ways Smart Animal and Manufacturing Work Can Mitigate Risks to Your Clinical Development Plan
February 18, 2013
For those of us focused on clinical trials management, it is easy to forget all of the work that happens before a potential treatment reaches the clinical trial stage of development. In this article, we will explore five key ways pre-IND animal and manufacturing work can impact your overall clinical development plan.
- Pharmacodynamics and an Early View into Efficacy
The primary goal of a phase I clinical trial is to demonstrate safety that allows progression to phase II. Of course, no one wants to move into costly human trials with a treatment that has a low probability of being effective. Pharmacodynamic studies look at the effect of the drug on the body (or in the case of an antibiotic on the effect of the drug on the target organism) and pharmacodynamic studies in animals provide an early indication of an efficacy target. By carefully selecting animal models that have the pharmacodynamic effect being pursued in humans you have a higher likelihood of getting meaningful safety information.
- ADME and Safety
Understanding the ADME (Absorption, Distribution, Metabolism, and Excretion) profile of your product as determined by preclinical pharmacokinetic studies is an important component for predicting safety issues as you move into human trials. The bioavailability of the product, where the product ends up, where and how the product is broken down, and how the product is excreted give you key insights into which physiological systems are likely to be impacted by your investigational product. If your product is broken down in the liver and excreted through the kidneys, you know these are two systems that should be monitored closely first in toxicology studies and then in human trials. Moreover, if you know that your drug is metabolized in your toxicology species similar to how it is metabolized in cultured human cells; for example, you will have more confidence that the toxicology of metabolites is adequately modeled in your toxicology program.
- Therapeutic Index and Your Dosing Strategy
Pharmacodynamic effects and toxicity are compared relative to dosing for something known as the therapeutic index. The therapeutic index is the range of doses between ED50 (the dose at which the pharmacodynamic effect elicited in animals is 50% of the maximal effect) and the MTD (the maximum tolerated dose). The therapeutic index as determined in preclinical studies is the starting point for your dose finding strategy as you move into human studies. It provides valuable information about a dose range with the highest probability of being both safe and effective in humans. Once a minimum effective dose is determined in animals the starting dose in humans should generally be one tenth of this dose, correcting for allometric scaling (i.e., quantifying the differing body sizes and shapes between two species and then using that mathematical relationship to adjust the dose from one species to the other).
- Development Stage Chemistry, Manufacturing, and Controls (CMC)
From short stability windows to manufacturing problems, issues on the CMC side of drug development can cause huge headaches and costly delays once clinical studies are underway. Here are a few things to be on the lookout for:
- Product stability: Although you can extend expiration dates as you go based on stability studies that are being conducted concurrently with clinical work, you want to make sure that initial stability data supports your early phase trials. You also want to ensure that plans for on-going stability work are coordinated to eventually support the entire duration of anticipated exposure to your product with clinical trial timelines.
- Storage and packaging: Find out early if special storage conditions are required. This is something you will have to consider when qualifying sites. Also, take a look at the packaging for concerns that investigators might have or problems that subjects might run into during the trial. If you are using unusual container closure systems or blister packs with complicated labeling, you may need to address these during investigator meetings and/or site training. Monitors should be aware of any of these concerns, so they are prepared to address questions and problems during site visits.
- Drug substance and drug product availability: Manufacturing delays come from numerous sources, and cannot always be avoided. By understanding the likelihood of these problems and through close communication between CMC experts and clinical operations staff, you can mitigate the impact of investigational product shortages and delays on clinical trial timelines.
- Meeting IND Requirements
Assuming you are planning trials in the US, you will need an IND to start any testing in humans and preclinical work is necessary to support an IND. While INDs do not require approval (no news is good news in this case), FDA may place you on a clinical hold if your preclinical work is substandard or incomplete. A clinical hold will stop you from starting any clinical trial activities and any activities you have started will have to be stopped. You will have to have sufficient pharmacology and toxicology data to convince FDA that the potential benefits outweigh the potential risks of moving studies into humans.
In the best of situations, the people working on the clinical development plan, the people responsible for the preclinical work, and the people who will execute the clinical work are able to work in a closely coordinated manner. By doing so, you can reduce time and costs associated with clinical development, eliminate poor product candidates early, and bring successful products to market quickly without sacrificing quality.